Regulatory Mechanisms of miRNA Strands Derived from a Single Precursor
One of the doctrines in the biogenesis of miRNAs claims that for each miRNA, only one strand, the guide strand (miRNA), is assembled into the active RISC; the other strand, called passenger or antisense in terms of relative polarity (miRNA*), is
V. Egea et al.
Fig. 1.1 Model of biogenesis and regulatory mechanisms of mature miRNAs. In the nucleus, miRNAs are transcribed from DNA and further processed by Drosha to a precursor hairpin miRNA (pre-miRNA). After being transported into the cytoplasm by a Exportin 5-dependent mechanism, the precursor miRNA is further cleaved by Dicer into mature miRNA heteroduplexes (miRNA- miRNA*). The processed miRNA strands can guide RISC with help of AGO2 to mRNA targets for translation inhibition, be inhibited in function by binding to the MREs of miRNA sponges or be extracellular transported into circulation. Cytoplasmic miRNAs can exit the cell enclosed within membranous vesicles as exosomes (generated from the fusion of MVB with the plasma membrane), microvesicles, or apoptotic bodies. miRNAs are released also vesicle-free associated with lipoproteins, such as HDL or RNA-binding proteins, such as AGO2 or NPM1. Once in circulation miRNAs are remarkably stable and regulate functions of the recipient cells. RISC RNA-induced silencing complex, AGO2 argonaute protein 2, MVB multivesicular body, NPM1 nucleophosmin1, coRNAs coding RNAs, ncoRNAs non-coding RNAs, cRNAs circular RNAs, HDL high-density lipoprotein
destroyed (Matranga et al. 2005). However, in contrast to previous beliefs, passenger strands may not always be cleaved but remain functional in translational processes thereby triggering synergistic or opposite cellular mechanisms as compared to that of the guide strand (Fig. 1.1) (Czech et al. 2009; Marco et al. 2012; Sakurai et al. 2011). Interestingly, coexisting miRNA-miRNA* pairs can either target the same mRNA molecule as described for miR-126, miR-582, and miR-17 or bind to different mRNAs as described for miR-28 (Zhang et al. 2013; Uchino et al. 2013; Yang et al. 2013; Almeida et al. 2012). Remarkably, miRNA-miRNA* pairs may play different roles in specific cell types within a tissue but ultimately may mediate the similar effects under disease condition (Thum et al. 2008; Bang et al. 2014). For instance, miR-21-5p is expressed and upregulated in cardiac fibroblasts of the failing heart and activates ERK-MAP kinase signaling, thus contributing to fibrosis, hypertrophy, and cardiac dysfunction (Thum et al. 2008). On the other hand, the guide strand miR-21-3p is increased in pericardial fluid of mice with left ventricular pressure overload-induced hypertrophy after aortic constriction (Bang et al. 2014); it is packed in fibroblast-derived exosomes and delivered to cardiomyocytes, where it mediates their hypertrophy (Bang et al. 2014). Thus, the combined regulatory roles of miRNA pairs should be taken into account in miRNA functional studies.